ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.1255C>A (p.Gln419Lys)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000251.3(MSH2):c.1255C>A (p.Gln419Lys)
Variation ID: 90583 Accession: VCV000090583.40
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p21 2: 47429920 (GRCh38) [ NCBI UCSC ] 2: 47657059 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jun 9, 2014 Feb 14, 2024 Sep 5, 2013 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000251.3:c.1255C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Gln419Lys missense NM_001258281.1:c.1057C>A NP_001245210.1:p.Gln353Lys missense NC_000002.12:g.47429920C>A NC_000002.11:g.47657059C>A NG_007110.2:g.31797C>A LRG_218:g.31797C>A LRG_218t1:c.1255C>A LRG_218p1:p.Gln419Lys P43246:p.Gln419Lys - Protein change
- Q419K, Q353K
- Other names
- p.Q419K:CAG>AAG
- Canonical SPDI
- NC_000002.12:47429919:C:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00080 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00019
Trans-Omics for Precision Medicine (TOPMed) 0.00029
Exome Aggregation Consortium (ExAC) 0.00061
1000 Genomes Project 0.00080
1000 Genomes Project 30x 0.00094
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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MSH2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
7207 | 7355 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Likely benign (1) |
reviewed by expert panel
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Sep 5, 2013 | RCV000076079.5 | |
Benign/Likely benign (4) |
criteria provided, multiple submitters, no conflicts
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Mar 11, 2022 | RCV000121568.13 | |
Benign/Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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Mar 5, 2021 | RCV000160643.10 | |
Likely benign (1) |
criteria provided, single submitter
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May 23, 2019 | RCV000759096.15 | |
Benign (1) |
criteria provided, single submitter
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Jan 29, 2024 | RCV001079969.8 | |
Benign/Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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May 28, 2019 | RCV000986666.6 | |
Benign (1) |
criteria provided, single submitter
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Mar 30, 2022 | RCV001030708.3 | |
Likely benign (1) |
no assertion criteria provided
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- | RCV001355791.2 | |
Likely benign (1) |
criteria provided, single submitter
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Apr 29, 2022 | RCV002504984.1 | |
Benign (1) |
criteria provided, single submitter
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Mar 7, 2022 | RCV003149745.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely benign
(Sep 05, 2013)
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reviewed by expert panel
Method: research
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Lynch Syndrome
Affected status: unknown
Allele origin:
germline
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International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Accession: SCV000107094.3
First in ClinVar: Dec 19, 2013 Last updated: Dec 24, 2022 |
Comment:
Multifactorial likelihood analysis posterior probability 0.001-0.049
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Benign
(Mar 07, 2022)
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criteria provided, single submitter
Method: clinical testing
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Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV003838301.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
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Likely benign
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 1
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001304345.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Likely benign
(May 23, 2019)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000211245.6
First in ClinVar: Feb 24, 2015 Last updated: Dec 19, 2017 |
Comment:
This variant is associated with the following publications: (PMID: 8690195, 22995991, 19419416, 23526924, 23741719, 11048710, 10469597, 23760103, 22290698, 17594722, 22283331, 25110875, 24728327, 12792735, 25106712, 17011982, … (more)
This variant is associated with the following publications: (PMID: 8690195, 22995991, 19419416, 23526924, 23741719, 11048710, 10469597, 23760103, 22290698, 17594722, 22283331, 25110875, 24728327, 12792735, 25106712, 17011982, 21155023, 15996210, 26951660, 24078570, 27487738, 26332594, 28580595, 29731845, 31386297) (less)
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Likely benign
(May 03, 2019)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002070660.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
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Benign
(Mar 30, 2022)
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criteria provided, single submitter
Method: research
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Hereditary breast ovarian cancer syndrome
Affected status: yes
Allele origin:
germline
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Cancer Genomics Group, Japanese Foundation For Cancer Research
Accession: SCV001193630.3
First in ClinVar: Apr 06, 2020 Last updated: May 07, 2022 |
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Benign
(Mar 11, 2022)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000888201.3
First in ClinVar: Mar 14, 2019 Last updated: Dec 31, 2022 |
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Likely benign
(Apr 29, 2022)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 1
Muir-Torré syndrome Mismatch repair cancer syndrome 2
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002801224.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Benign
(Jan 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000260558.11
First in ClinVar: Mar 24, 2015 Last updated: Feb 14, 2024 |
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Likely benign
(Apr 14, 2015)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000537420.1
First in ClinVar: Mar 24, 2017 Last updated: Mar 24, 2017 |
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Benign
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 1
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001135724.1
First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020 |
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Benign
(Mar 19, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000917686.3
First in ClinVar: Jun 02, 2019 Last updated: Apr 13, 2021 |
Comment:
Variant summary: MSH2 c.1255C>A (p.Gln419Lys) results in a conservative amino acid change located in the core domain (IPR007696) of the encoded protein sequence. Five of … (more)
Variant summary: MSH2 c.1255C>A (p.Gln419Lys) results in a conservative amino acid change located in the core domain (IPR007696) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00057 in 252292 control chromosomes, predominantly at a frequency of 0.0075 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 13 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00057), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1255C>A has been reported in the literature in individuals affected with Lynch Syndrome (e.g. Tang_2009, Yap_2009) or Breast Cancer (e.g. Shin_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Co-occurrence with a pathogenic variant has been reported (BRCA2 c.6952C>T, p.R2318*), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. (less)
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Benign
(Mar 05, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002528825.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Likely benign
(Nov 16, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000213572.6
First in ClinVar: Mar 24, 2015 Last updated: Nov 29, 2022 |
Comment:
This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, … (more)
This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Number of individuals with the variant: 1
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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Carcinoma of colon
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001550774.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The MSH2 p.Gln419Lys variant was identified in 8 of 10182 proband chromosomes (frequency: 0.001) from individuals or families with gastric cancer, colorectal and stomach cancer … (more)
The MSH2 p.Gln419Lys variant was identified in 8 of 10182 proband chromosomes (frequency: 0.001) from individuals or families with gastric cancer, colorectal and stomach cancer and was present in 2 of 2186 control chromosomes (frequency: 0.001) from healthy individuals (Fan 2005, Kang 2015, Lee 2005, Tang 2009, Bodian 2014). The variant was also identified in dbSNP (ID: rs63750006) as With Likely benign, Pathogenic allele, ClinVar (classified as likely benign by GeneDx, Ambry Genetics, Color Genomics, InSight; classified as benign by Invitae), Clinvitae, MutDB, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database, databases. The variant was not identified in the COGR, Cosmic, or UMD-LSDB. The variant was identified in control databases in 147 of 277056 chromosomes (1 homozygous) at a frequency of 0.001 (Genome Aggregation Database Feb 27, 2017). It was identified in the following populations: East Asian in 147 of 18866 chromosomes (freq: 0.01); but not observed in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, Finnish, and South Asian populations. The p.Gln419 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. One study suggested that the glutamine to lysine substitution may influence the conformation of this domain and the function of the gene. And predispose humans to gastric cancer (Fan 2005). In addition, Drotschmann (1999) studied yeast carrying Gln430Lys (the putative equivalents of Gln419Lys in hMSH2), which yielded significant mutator effects, indicating a functional defect and may predispose humans to disease. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. (less)
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not provided
(Sep 19, 2013)
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no classification provided
Method: reference population
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AllHighlyPenetrant
Affected status: unknown
Allele origin:
germline
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ITMI
Accession: SCV000085764.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 |
Observation 1:
Ethnicity/Population group: Whole_cohort
Observation 2:
Ethnicity/Population group: African
Observation 3:
Ethnicity/Population group: African_European
Observation 4:
Ethnicity/Population group: Central_Asian
Observation 5:
Ethnicity/Population group: East_Asian
Observation 6:
Ethnicity/Population group: European
Observation 7:
Ethnicity/Population group: Hispanic
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Detection of Germline Mutations in Breast Cancer Patients with Clinical Features of Hereditary Cancer Syndrome Using a Multi-Gene Panel Test. | Shin HC | Cancer research and treatment | 2020 | PMID: 32019277 |
Analysis of human MutS homolog 2 missense mutations in patients with colorectal cancer. | Zhang X | Oncology letters | 2018 | PMID: 29731845 |
Usefulness of PET/CT for early detection of internal malignancies in patients with Muir-Torre syndrome: report of two cases. | Ishiguro Y | Surgical case reports | 2017 | PMID: 28537014 |
Oligonucleotide-directed mutagenesis screen to identify pathogenic Lynch syndrome-associated MSH2 DNA mismatch repair gene variants. | Houlleberghs H | Proceedings of the National Academy of Sciences of the United States of America | 2016 | PMID: 26951660 |
Identification of Medically Actionable Secondary Findings in the 1000 Genomes. | Olfson E | PloS one | 2015 | PMID: 26332594 |
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
Lynch-like syndrome: characterization and comparison with EPCAM deletion carriers. | Kang SY | International journal of cancer | 2015 | PMID: 25110875 |
Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing. | Bodian DL | PloS one | 2014 | PMID: 24728327 |
Missense mutations of MLH1 and MSH2 genes detected in patients with gastrointestinal cancer are associated with exonic splicing enhancers and silencers. | Zhu M | Oncology letters | 2013 | PMID: 23760103 |
Prevalence of pathological germline mutations of hMLH1 and hMSH2 genes in colorectal cancer. | Li D | PloS one | 2013 | PMID: 23526924 |
An informatics approach to analyzing the incidentalome. | Berg JS | Genetics in medicine : official journal of the American College of Medical Genetics | 2013 | PMID: 22995991 |
Classification of mismatch repair gene missense variants with PON-MMR. | Ali H | Human mutation | 2012 | PMID: 22290698 |
High-resolution melting analyses for gene scanning of APC, MLH1, MSH2, and MSH6 associated with hereditary colorectal cancer. | Obul J | Genetic testing and molecular biomarkers | 2012 | PMID: 22283331 |
Racial differences in MLH1 and MSH2 mutation: an analysis of yellow race and white race based on the InSiGHT database. | Wei W | Journal of bioinformatics and computational biology | 2010 | PMID: 21155023 |
Germ line MLH1 and MSH2 mutations in Taiwanese Lynch syndrome families: characterization of a founder genomic mutation in the MLH1 gene. | Tang R | Clinical genetics | 2009 | PMID: 19419416 |
Recurring MLH1 deleterious mutations in unrelated Chinese Lynch syndrome families in Singapore. | Yap HL | Familial cancer | 2009 | PMID: 18726168 |
Accurate classification of MLH1/MSH2 missense variants with multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR). | Chao EC | Human mutation | 2008 | PMID: 18383312 |
Functional analysis helps to clarify the clinical importance of unclassified variants in DNA mismatch repair genes. | Ou J | Human mutation | 2007 | PMID: 17594722 |
Variations in exon 7 of the MSH2 gene and susceptibility to gastrointestinal cancer in a Chinese population. | Fan Y | Cancer genetics and cytogenetics | 2006 | PMID: 17011982 |
Germline mutations and polymorphic variants in MMR, E-cadherin and MYH genes associated with familial gastric cancer in Jiangsu of China. | Zhang Y | International journal of cancer | 2006 | PMID: 16929514 |
Clinical and molecular characteristics of hereditary non-polyposis colorectal cancer families in Southeast Asia. | Lee SC | Clinical genetics | 2005 | PMID: 15996210 |
Oncogenic pathway of sporadic colorectal cancer with novel germline missense mutations in the hMSH2 gene. | Yamada K | Oncology reports | 2003 | PMID: 12792735 |
Mutator phenotypes of common polymorphisms and missense mutations in MSH2. | Drotschmann K | Current biology : CB | 1999 | PMID: 10469597 |
http://www.insight-database.org/classifications/index.html?gene=MSH2&variant=c.1255C%3EA | - | - | - | - |
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Text-mined citations for rs63750006 ...
HelpRecord last updated Feb 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.